Yu Lan, Shang Zeng-Fu, Abdisalaam Salim, Lee Kyung-Jong, Gupta Arun, Hsieh Jer-Tsong, Asaithamby Aroumougame, Chen Benjamin P C, Saha Debabrata
Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA School of Radiation Medicine and Protection, Medical College of Soochow University; Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Suzhou, Jiangsu 215123, China.
Nucleic Acids Res. 2016 Oct 14;44(18):8842-8854. doi: 10.1093/nar/gkw746. Epub 2016 Aug 27.
Defects in kinetochore-microtubule (KT-MT) attachment and the spindle assembly checkpoint (SAC) during cell division are strongly associated with chromosomal instability (CIN). CIN has been linked to carcinogenesis, metastasis, poor prognosis and resistance to cancer therapy. We previously reported that the DAB2IP is a tumor suppressor, and that loss of DAB2IP is often detected in advanced prostate cancer (PCa) and is indicative of poor prognosis. Here, we report that the loss of DAB2IP results in impaired KT-MT attachment, compromised SAC and aberrant chromosomal segregation. We discovered that DAB2IP directly interacts with Plk1 and its loss inhibits Plk1 kinase activity, thereby impairing Plk1-mediated BubR1 phosphorylation. Loss of DAB2IP decreases the localization of BubR1 at the kinetochore during mitosis progression. In addition, the reconstitution of DAB2IP enhances the sensitivity of PCa cells to microtubule stabilizing drugs (paclitaxel, docetaxel) and Plk1 inhibitor (BI2536). Our findings demonstrate a novel function of DAB2IP in the maintenance of KT-MT structure and SAC regulation during mitosis which is essential for chromosomal stability.
细胞分裂过程中动粒微管（KT-MT）附着和纺锤体组装检查点（SAC）的缺陷与染色体不稳定性（CIN）密切相关。CIN与致癌作用、转移、预后不良以及癌症治疗耐药性有关。我们之前报道过DAB2IP是一种肿瘤抑制因子，在晚期前列腺癌（PCa）中经常检测到DAB2IP缺失，这预示着预后不良。在此，我们报道DAB2IP缺失会导致KT-MT附着受损、SAC功能受损以及染色体异常分离。我们发现DAB2IP直接与Plk1相互作用，其缺失会抑制Plk1激酶活性，从而损害Plk1介导的BubR1磷酸化。DAB2IP缺失会降低有丝分裂进程中BubR1在动粒处的定位。此外，DAB2IP的重建增强了PCa细胞对微管稳定药物（紫杉醇、多西他赛）和Plk1抑制剂（BI2536）的敏感性。我们的研究结果证明了DAB2IP在有丝分裂过程中维持KT-MT结构和SAC调控方面的新功能，这对染色体稳定性至关重要。
